Project Summary: The brain is an important target organ for thyroid hormone (T3) actions and T3 plays important roles in the brain function and neurodevelopment. Thyroid hormone (T3) exerts its divergent physiological functions by binding to thyroid hormone receptors (TRs). Previous studies, in general or in the brain as well, mostly focused on the classical mechanism of TR to regulate gene expression by binding to specific thyroid hormone response elements (DMA sequence) in the promoter region of target gene. The view that transcriptional regulation is the predominant regulatory mechanism, however, has been increasingly challenged by the discovery of ever-increasing examples of post-transcriptional mechanisms for regulating gene expression. More recently we found that TRs are also RNA binding proteins and a novel RNA binding domain in the thyroid hormone receptor was necessary and sufficient for thyroid hormone receptor binding to the steroid receptor RNA activator (SRA). We therefore hypothesize that TR not only functions as transcriptional factor but may also regulate gene expression at post-transcriptional levels through TR-messenger RNA (mRNA) interacting pathways. However, the molecular mechanism(s) and physiological function(s) of TR-mRNA interaction remain unknown, and the TR associated mRNAs in the brain remain to be characterized. The purpose of this project is to identify the potential TR associated subsets of mRNAs in the brain using biochemical (immunoprecipition) and genetic (cRNA microarray, genome-wide analysis of TR-mRNA binding profiles) approaches, which will provide fundamental tools to reveal how these mRNAs interacting with TR could facilitate to regulate the specific gene expression related to brain function and neurodevelopment (or disease) at post-transcriptional level. The identification and characterization of TR associated subsets of mRNA in vivo will provide novel insight of regulation of brain specific gene expression through post-transcriptional pathway related to brain functions. Relevance: The goal of this study is to identify and characterize the subset of mRNAs associated with thyroid hormone receptors in the brain via biochemical and genome-wide analysis of TR-mRNA binding profiles. The findings of TR targeted mRNAs will reveal novel functions of TR to regulate gene expression at post-transcriptional levels related to the brain function and neurodevelopment.. [unreadable] [unreadable]